1. Field of the Invention
The present disclosure relates to a pharmaceutical composition for preventing or treating neurodegenerative diseases, and more particularly, the present disclosure relates to a pharmaceutical composition for preventing or treating neurodegenerative diseases including an agent capable of suppressing expression or activity of SHP-1/-2 or FcγRIIB, a method of preventing or treating neurodegenerative diseases by administering the pharmaceutical composition, a method of screening for a therapeutic agent for neurodegenerative diseases, a diagnostic composition for neurodegenerative diseases, a diagnostic kit for neurodegenerative diseases including the diagnostic composition, and a method of diagnosing neurodegenerative diseases using the diagnostic composition or kit.
2. Description of the Related Art
The exact etiology of Parkinson's disease remains unknown, but familial Parkinson's disease is known to be caused by many genetic defects in alpha-synuclein (α-synuclein), parkin, PINK1, DJ-1, LRRK2, etc. Until now, it has been known that oxidative stress, mitochondria disorders, and dysfunction of intracellular protein-clearance mechanism are also considered to cause Parkinson's disease. It is believed that Parkinson's disease is caused by environmental factors as well as genetic factors. Occurrence of Parkinson's disease is diagnosed based on clinical symptoms, and Parkinson's disease is also treated merely by conservative therapy for alleviating symptoms rather than radical therapy. Accordingly, it is urgent to accurately understand the etiology and to find an appropriate therapy corresponding thereto.
Alpha-synuclein (α-synuclein; α-syn) is a major cytoplasmic protein of Lewy body found in patients with Parkinson's disease, and mainly distributed in presynaptic terminals of neurons. Alpha-synuclein is known to be highly expressed throughout the brain tissue. Alpha-synuclein is known to cause other neurodegenerative diseases such as dementia with Lewy bodies, multiple system atrophy, etc. as well as Parkinson's disease. All diseases associated with abnormal accumulation of alpha-synuclein are generally called synucleinopathy, and alpha-synuclein has been actively studied as a common therapeutic target for the diseases.
Further, alpha-synuclein may form aggregates, and it has been suggested that changes of monomeric alpha-synuclein into aggregates may be a main cause of Parkinson's disease. Further, duplication and triplication of alpha-synuclein gene were found in familiar Parkinson's disease, and therefore, many efforts have been actively made to find functions of alpha-synuclein. For example, as a pharmaceutical composition targeting aggregated alpha-synuclein, a pharmaceutical composition for treating Parkinson's disease including Longan Arillus extract as an active ingredient, which is able to significantly protect dopaminergic neurons from neurotoxic effects by alpha-synuclein aggregation, was developed (Korean Patent No. 1189191). However, specific receptors of alpha-synuclein and mechanisms thereof have not been clarified yet.
Meanwhile, change of protein monomers into aggregates occurs in amyloid beta (Aβ) and tau of Alzheimer's disease, mutated huntingtin of Huntington's disease, prion of prion disease, etc., as well as in alpha-synuclein of Parkinson's disease. This change is considered as a common cause of neurodegenerative diseases, and many studies have been actively conducted to treat neurodegenerative diseases by inhibiting the change.
Thereafter, interest in the intracellular delivery of alpha-synuclein is rapidly growing. It is reported that aggregated alpha-synuclein enters neighboring cells to be involved in formation of Lewy bodies and cell death of neighboring cells, like prions in prion disease which bind with normal prions expressed in normal neurons to form aggregates. When pathogenesis of Parkinson's disease by extracellular alpha-synuclein is inferred from the above concept, it is likely that various forms of alpha-synuclein released from cells act on neighboring microglias and activate them to show neuronal toxicity, and furthermore, propagation of alpha-synuclein to neighboring neurons causes direct toxicity or induces formation of Lewy bodies to trigger a series of cytotoxic events.
Therefore, receptors or structures involved in intracellular signaling by extracellular alpha-synuclein may be important clues to elucidate the pathogenesis of many neurodegenerative diseases, and also very interesting in terms of establishing a new therapeutic strategy. However, there have been few studies thereof.
Under this background, the present inventors have made considerable efforts to investigate the mechanism underlying propagation of alpha-synuclein to neighboring cells, and as a result, they found that SHP-1/-2 activation is involved in propagation of alpha-synuclein, and SHP-1/-2 activation is mediated by a receptor for alpha-synuclein, FcγRIIB and therefore, expression or activity of SHP-1/-2 or FcγRIIB is suppressed to inhibit progression of many neurodegenerative diseases caused by alpha-synuclein, thereby completing the present invention.